Host: The Japanese Society of Toxicology
Name : The 47th Annual Meeting of the Japanese Society of Toxicology
Date : 2020 -
KEAP1-NRF2 system is a sulfur-based cytoprotection mechanism. KEAP1 utilizes multiple cysteine residues for sensing electrophiles, whereas NRF2 activates various genes regulating sulfur-involving reactions. Although NRF2 enhances mitochondrial activity, a precise mechanism has not been fully understood. Based on our recent discovery that mitochondrial sulfur metabolism makes a substantial contribution to generation of the mitochondrial membrane potential, we hypothesized that NRF2 promotes the mitochondrial activity through promoting the sulfur metabolism. Since SLC7A11 encoding a cystine transporter, xCT, is a well-known NRF2 target gene, NRF2 was likely to enhance the mitochondrial sulfur metabolism to generate persulfides potentially by increasing the supply of their substrate, cysteine. Indeed, xCT inhibition decreased the mitochondrial membrane potential. In addition, we found that SQRDL, encoding sulfide-quinone oxidoreductase (SQR), is directly activated by NRF2. To examine the in vivo contribution of SQR, we generated SQR mutant mice, which express mutant SQR lacking a mitochondrial localization signal. The mutant mice exhibited compensatory facilitation of β-oxidation. Although the mutant mice died by 10 weeks after birth with normal diet, high-fat diet extended their lifespan. Our detailed sulfur metabolome analysis revealed that SQR effectively catalyzes proton and electron transfer from hydropersulfides in addition to sulfide to the mitochondrial electron transport chain (ETC). Thus, SQR makes an essential contribution to the maintenance of the mitochondrial membrane potential by mediating proton/electron supply to the ETC. These results suggest that one of the mechanisms for NRF2-dependent mitochondrial activation is the facilitation of sulfur respiration in mitochondria following the increased cystine uptake.
